Several parasites responsible for mammalian diseases are dependent on cysteine protease for various life-cycle functions Inhibition of these proteases can be useful in the treatment and/or prevention of these parasitic diseases, see Lecaille, F., et al, Chem. Rev., 102, 4459-4488, 2002.
Cruzipain is a cysteine protease enzyme present in Trypanosoma cruzi and is thought to play an important role in all stages of the parasite's life cycle. The enzyme is highly expressed in the epimastigote stage where it is primarily a lysosomal enzyme and may be involved in protein digestion during differentiation to the infective metacyclic trypomastigote stage. Identification of cruzipain in the membrane of the trypomastigote implicates this enzyme in the penetration of the parasite into the host cell. Cruzipain is also found in the membranes of the amastigote form of the parasite, see Cazzulo, J. J., et al, Current Pharmaceutical Design, 7, 1143-1156, 2001. Cruzipain efficiently degrades human IgG, which may play a protective role for the parasite by preventing antigen presentation and thus reducing the host immune response. Based on these observations, it has been proposed that cruzipain is a valid drug target for chemotherapy of Chagas disease. Cruzipain has been reported to exist in at least two polymorphic sequences, known as cruzipain 1 and cruzipain 2, both of which may be involved in the viability of Trypanosoma cruzi (Lima, et al, Molecular & Parasitology 114, 41-52, 2001).
The use of cysteine protease inhibitors for the treatment of Chagas disease and African trypanosomaisis has been shown by the observation that irreversible inhibitors of cruzipain can cure Chagas disease in mouse models, see Engel, J., et al, J. Exp. Chem., 188, 725-734, 1998.
A similar role for the cysteine protease trypanopain-Tb has been proposed in the life-cycle of Trypanosoma brucei, the parasite responsible for African trypanosomaisis, or sleeping sickness.
A similar parasite, T. congolense, is responsible for the bovine disease trypanosomiasis. Congopain is the analogous cysteine protease to cruzipain in this parasite.
Falcipain is an important cysteine protease in Plasmodium falicparum. This enzyme is reported to be important in the degradation of host hemoglobin in parasite food vacuoles. The processing of hemoglobin is essential to the growth of the parasite, thus an inhibitor of falcipain should be useful as a treatment for malaria.
Two cysteine proteases, SmCL1 and SmCL2, are present in the human blood fluke Schistosoma mansoni. SmCL1 may play a role in the degradation of host hemoglobin, while SmCL2 may be important to the reproductive system of the parasite (Brady, C. P., et al, Archives of Biochemistry and Biophysics, 380, 46-55, 2000) Inhibition of one or both of these proteases may provide an effective treatment for human schistosomiasis.
LmajcatB and CP2.8ΔCTE are important cysteine proteases of the parasitic protazoa Leishmania major and Leishmania mexicanus respectively, see Alves, L. C., et al, Eur. J. Biochem, 268, 1206-1212, 2001 Inhibition of these enzymes may provide a useful treatment for leishmaniasis.
CP2 is a major cysteine protease of the flagellate Giardia lamblia which may be important to encystation and replication of the parasite (DuBois, K. N. et al, J. Biol. Chem., 283, 18024-18031, 2008) Inhibition of CP2 or the other 26 known clan CA protease in this parasite may provide a useful treatment of giardiasis.
Two cysteine proteases coded by AcCP-1 and AcCP-2 have been found in the hookworm Ancylostoma caninum (Harrop, S. A. et al, Mol Biochem Parasitol. 71, 163-71, 1995. Inhibition of these proteases may provide a useful treatment of Ancyclostoma infection.
Cysteine proteases are also known to be present in Trichomonas vaginalis (Jane R. Schwebke, J. R. and Burgess D., Clinical Microbiology Reviews, 17, 794-803, 2004.). Inhibition of these proteases may provide a treatment for the venereal disease trichomoniasis associated with this parasite.
Entamoeba histolytica is the protozoan causative agent of human amoebiasis. It is known to contain the cysteine protease EhCP112 (Garcia-Rivera, G. et al, Molecular Microbiology 33, 556-568, 1999). Use of a protease inhibitor may be useful in the treatment of amoebiasis.
A cysteine protease has been identified in the intestinal parasite Cryptosporidium parvum (Nesterenko M. W. et al, Microbios 83, 77-88 1995, Formey J. R. et al, J. Parasitol. 82, 889-92, 1996). A cysteine protease inhibitor could be a useful treatment of cryptosporidiosis. Indeed, treatment of mice with the irreversible inhibitor K-777 results in clearance of the parasite from immunocompromised mice (Ndao et al, Parasitology 2008 135, 1151-6, 2008).
A number of Eimeria parasites can lead to disease in animals of agricultural importance such as chickens and cattle (Barta. J. R. et al, J. Parasitol. 83, 262-71, 1997). Cysteine protease inhibitors may provide a treatment for mammals infected with E. bovis, E. necatrix, E. tenella, E. mitis, E. mivati, E. praecox, E. maxima, E. brumetti, and E. acervuline 
Numerous other parasites have been reported to be dependent on cysteine proteases (Sajid, M., and McKerrow, J. H. Molecular and Biochemical Parasitology, 120, 1-21, 2002) and thus may be treated with inhibitors of these proteases. These parasites include Plasmodium chabaudi, Plasmodium Berghei, Naegleria fowleri, Theileria parva, Toxoplasma gondii, Strongyloides stercoralis, Ascaris suum, Haemonchus contortus, Necator americanus, Taenia saginata, Gymnorhynchus gigas, Spirometra mansonoidese, Diplostomum pseudospathaceum, Onchercerca volvulus, Fasciaola hepatica and Dilofilaria immitis. 
The present invention relates to compounds that are capable of treating and/or preventing mammalian parasitic diseases in which the parasite utilizes a critical cysteine protease from the papain family.